Tuft cells are rare, chemosensory epithelial cells present in various tissues, including the respiratory and gastrointestinal tracts. Recent studies have revealed their significant role in cancer biology, particularly through the expression of the transcription factor POU2F3, which serves as a master regulator of tuft cell lineage. In several cancer types, including small cell lung cancer, gastric cancer, and breast cancer, POU2F3 expression defines a distinct molecular subtype termed “tuft cell-like” tumors. These tumors exhibit unique transcriptional programs and altered tumor-immune interactions, contributing to their distinct therapeutic sensitivities. In this review, we first analyze the expression patterns of POU2F3 across cancer types using the TCGA datasets, revealing differential expression profiles and supporting the classification of tuft cell-like subtypes. We further explore cancer-type-specific signaling pathways regulating tuft cell differentiation and function, such as IL-25, acetylcholine, and taste receptor-related pathways. Finally, we propose that tuft cell-like signatures may serve as promising biomarkers for diagnosis, prognosis, and treatment stratification. Understanding the tuft cell-like–POU2F3 axis could open new avenues for targeted therapies in lineage-defined cancers.

Despite the availability of efficacious vaccines, COVID-19 persists and our knowledge of how SARS-CoV-2 infection affects host transcriptomics remains incomplete. Transcriptome analysis, which has progressed our understanding of the patient response to SARS-CoV-2 infection, can be enhanced by considering chimeric transcript expression. Here we assess and characterize chimeric RNAs found in the whole blood of 178 COVID-19 patients. STAR-Fusion, SOAPfuse, and EricScript were used to detect chimeric RNAs resulting in over 30,000 predictions with approximately 500 high-confidence predictions that were found by more than one software and filtered based on exon annotations around the chimeric splice junction. GO term enrichment performed on the 5′ and 3′ parental genes of chimeric RNAs found in severe and critical patients resulted in pathways known to be affected in these patients, such as erythroid differentiation. Motif enrichment analysis of sequences proximal to chimeric splice junctions found in COVID-19 patients versus those found in GTEx whole blood revealed two RNA binding proteins previously implicated with coronavirus infection, PTBP1 and SFPQ. We discovered a chimeric RNA that correlated with COVID-19 disease status and appeared to be dependent upon a loss of PTBP1’s function as a splicing repressor. Overall, we found over 350 novel COVID-19-specific chimeric RNAs not detectable in GTEx whole blood that may also serve as biomarkers for viral infection.

Gene fusions are appreciated as ideal cancer biomarkers and therapeutic targets. Chimeric RNAs are traditionally thought to be products of gene fusions, and thus, also cancer-specific. Recent research has demonstrated that chimeric RNAs can be generated by intergenic splicing in the absence of gene fusion, and such chimeric RNAs are also found in normal physiology. These new findings challenge the traditional theory of chimeric RNAs exclusivity to cancer, and complicates use of chimeric RNAs in cancer detection. Here, we provide an overview of gene fusions and chimeric RNAs, and emphasize their differences. We note that gene fusions are able to generate chimeric RNAs in accordance with the central dogma of biology, and that chimeric RNAs may also be able to influence the generation of the gene fusions per the “horse before the cart” hypothesis. We further expand upon the “horse before the cart” hypothesis, summarizing current evidence in support of the theory and exploring its potential impact on the field.